Arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines as α-adrenergic receptor antagonist with uro-selective activity.

A series of arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines was synthesized to develop new α-adrenoceptor antagonists with uroselective profile. Biological evaluation for α- and α-adrenorecepor showed that tested compounds 13-37 displayed high-to-moderate affinity for the α-adrenoceptor (K=34-348nM) and moderate selectivity over α-receptor subtype. Compounds with highest affinity and selectivity for α-adrenoceptor were evaluated in vitro for their intrinsic activity toward α- and α-adrenoceptor subtypes. All compounds behaved as antagonists at both α-adrenoceptor subtypes, displaying 2- to 6-fold functional preference to α-subtype. Among them, N-{1-[2-(2-methoxyphenoxy)ethyl]piperidin-4-yl}isoquinoline-4-sulfonamide (25) and 3-chloro-2-fluoro-N-{[1-(2-(2-isopropoxyphenoxy)ethyl)piperidin-4-yl]methyl}benzene sulfonamide (34) displayed the highest preference to α-adrenoceptor. Finally, compounds 25 and 34 (2-5mg/kg, iv), in contrast to tamsulosin (1-2mg/kg, iv), did not significantly decrease systolic and diastolic blood pressure in normotensive anesthetized rats to determine their influence on blood pressure.